PROJECT SUMMARY Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a potentially lethal inherited disorder that affects approximately 1/20,000 children and is clinically and genetically distinct from the more common Autosomal Dominant PKD (ADPKD). ARPKD is characterized by diffuse renal microcysts resulting from fusiform dilatations of the collecting tubules. Morbidity and mortality is significant: only 70% of ARPKD children survive the neonatal period and 40% progress to end-stage renal disease (ESRD) by age 15 years. There are currently no disease-specific clinically-available therapies for ARPKD and treatment is directed at management of chronic kidney disease (CKD) complications. Several novel therapies have, however, shown promise in both ARPKD animal models and adult ADPKD patients. Unfortunately, the major roadblock for implementing clinical trials in ARPKD patients is the absence of sensitive measures of ARPKD kidney disease progression. Conventional measures of kidney disease progression, such as declines in estimated glomerular filtration rate (eGFR) are variable in ARPKD, and GFR may remain unchanged despite ongoing kidney damage. Imaging assessments of kidney volume, which have been successfully utilized in ADPKD clinical trials, have limited applicability to ARPKD, as kidney size stabilizes over time despite worsening cystic disease. Therefore, alternative markers are needed to stage and monitor ARPKD kidney disease progression. As part of funded preclinical and clinical studies, our multidisciplinary imaging team has identified T2-MRI as a sensitive measure of ARPKD progression. In studies in the PCK rat and bpk mouse models, we utilized high resolution T2-MRI to establish renal cystic burden as an accurate and sensitive marker for ARPKD progression and therapeutic response. In preliminary studies in ARPKD patients, we show that ARPKD patients have increased mean kidney T2-MRI values in comparison to healthy control subjects and demonstrate phenotypic variations in mean kidney T2 values that are consistent with differences in kidney disease severity. Our imaging team has also pioneered novel Magnetic Resonance Fingerprinting (MRF) technologies that are resistant to motion artifacts and allow for rapid, simultaneous acquisition of multiple imaging parameters. The overall objective of this proposal is to establish mean kidney T2 values as a sensitive, quantitative MRI biomarker to stage and longitudinally monitor ARPKD kidney disease. We will utilize these techniques to obtain both cross- sectional and longitudinal assessments of kidney disease in pediatric and young adult ARPKD patients recruited from across the U.S. The proposed studies, conducted at two US sites, will be the first to systematically apply these quantitative MRI techniques to assess renal cystic burden in ARPKD patients, with the long term goal of developing MRI biomarkers for ARPKD kidney disease that can be used to identify patients at high risk for disease progression and to serve as outcome measures for eventual clinical trials for ARPKD patients.